The aim of the research plan is to evaluate pathophysiological factors and biochemical mechanisms that contribute to give cellular damage in the brain in conditions primarily interfering with cerebral energy metabolism. One goal of the research is to define prophylactic measures and therapeutic principles that may minimize or prevent the development of irreversible neuronal damage. In order to achieve these aims, animal models have been worked out that allow studies of reversible and irreversible forms of cerebral hypoxia and ischemia, hypoglycemia and status epilepticus, and these models have been characterized in some detail with respect to biochemical and circulatory alterations. Our plans are to use these models for studying (1) the mechanisms of cell damage, specifically whether the final damage which results from transient ischemia or hypoxia is at least partly incurred in the reoxygenation period and, if this is the case, whether this is mainly due to abnormalities of blood flow, or to biochemical processes within the tissue, (2) if tissue injury in conditions of hypoxia and ischemia is significantly influenced by tissue acidosis, (3) if selective vulnerability of neuronal populations is related to regional differences in metabolic rate, and (4) if oxidative mechanisms, notably those involving lipid peroxidation by free radicals, are responsible for cell damage. The impact of the insults and the extent of final damage, will be evaluated by monitoring electrophysiological function, by measuring global and regional blood flow, oxygen and substrate utilization, as well as tissue concentrations of labile metabolites reflecting cellular energy state, by assessing concentrations and turnover of monoamines, by measuring respiratory capacity and oxidative phosphorylation in isolated mitochondria, and by histopathology. Oxidative damage to cellular lipids will be evaluated from phospholipids in whole tissue and isolated mitochondria, and by studying changes in tissue concentrations of free radical scavengers.